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RNA-dependent RNA polymerase activity and effect on host inflammatory response of Hepatitis C Virus(HCV)NS5B.

Research Project

Project/Area Number 11694257
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionKANAZAWA UNIVERSITY

Principal Investigator

MURAKAMI Seishi  Dept.Mol.Oncology, Cancer Res.Inst., KANAZAWA UNIVERSITY Professor, がん研究所, 教授 (90019878)

Co-Investigator(Kenkyū-buntansha) HAYASHI Naoyuki  Dept.Mol.Oncology, Cancer Res.Inst., KANAZAWA UNIVERSITY Research Associate, がん研究所, 助手 (50253456)
YOSHIOKA Katsuji  Dept.Mol.Cell Biol., Cancer Res.Inst., KANAZAWA UNIVERSITY Associate Professor, がん研究所, 助教授 (60200937)
SUDA Takashi  Center for Mol.Target Drugs Cancer Res.Inst., KANAZAWA UNIVERSITY Professor, がん研究所, 教授 (70250090)
NOMURA Takahiro  Dept.Mol.Oncology, Cancer Res.Inst., KANAZAWA UNIVERSITY Research Associate, がん研究所, 助手 (80115261)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥6,100,000 (Direct Cost: ¥6,100,000)
Fiscal Year 2000: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1999: ¥3,300,000 (Direct Cost: ¥3,300,000)
KeywordsHCV NS5B / RNA-dependent RNA polymerase(RdRP) / alanine scanning / RNA binding / HCV infection / activation of NF-kB / HCV惑染 / C型肝炎ウイルス / RNA依存RNA合成酵素 / MAPキナーゼ / RNA複製 / 核小体
Research Abstract

Eradication of HCV has been expected to reduce or prevent incidence of HCC.HCV NS5B, RNA-dependent RNA polymerase(RdRP), is a target to inhibit HCV replication. We constructed a series of clustered and point alanine substitution mutations of NS5B and examined the effects of the mutations on functions of NS5B.The results are followings. 1)5 amino acid residues were newly identified to be indispensable for RdRP activity(Hepatology, in press). All are outside of the motifs conserved among RdRPs and reverse transcriptases. The result may provide desigins for specific inhibitors for HCV RdRP.2)RdRP activity of NS5B requires not template binding but template/primer. All mutants negative in the template binding are positive in RdRP activity except Y276A which is both negative in template/primer binding and RdRP activity. 3)The two residues apart from the catalytic center of RdRP activity are important for oligomerization of NS5B which we could find to be essential for RdRP activity. 4)Overexpression of NS5B activated AP-1 and NF-kB critical for acute inflammatory response, but a NS5B sequence could not be specified to be responsible for the activation which is influenced by expression level of NS5B.NS5B may modulate inflammatory responses but it remains addressed whether our observation has biological relevance in chronic HCV infection where a low amount of NS5B with coordinated expression of the other NS proteins is expected.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (71 results)

All Other

All Publications (71 results)

  • [Publications] Tul, DY., et al.: "Incidence of hepatocellular carcinoma in the transgenic mice expressing hepatitis B virus X-protein."J.Hepatol.. 31. 123-132 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nomura, T., et al.: "Human Hepatitis B Virus X protein is detectable in nuclei of transfected cells, And active for transactivation."Biochim.Biophys.Acta.. 1453. 330-340 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohno, H., et al.: "Human-Hepatitis B Virus X protein augments the DNA binding of nuclear Factor for IL& through its basic leucine zipper domain."J.Med.Viol.. 58. 11-18 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Murakami, S.: "Hepatitis B Virus X protein : Structure, Functions and Biological Roles."Intervirology. 42. 81-99 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 村上清史: "B型肝炎ウイルスX蛋白の発現と機能"生化学. 71.11. 1309-1326 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kuwano, K., et al.: "Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis."J.Clin.Invest.. 104. 13-19 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Koyano, S., et al.: "A novel Jun N-terminal kinase(JNK)-binding protein that enhances the activation of JNK by MEK kinase 1 and TGF-activated kinase 1"FEBS Lett.. 457. 385-388 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ito, M.Et al.: "JSAP1, a novel Jun N-terminal kinase(JNK)that functions as a scaffold factor in the JNK signaling pathway."Mol.Cell.Biol.. 19. 7539-7548 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takao, N., et al.: "Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellar response to ionizing radiation."Oncogene. 18. 7002-7009 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Zhang, Y., et al.: "Immunosuppressant FK506 activates NFkB through the proteasome-mediated degradation of IkB"J.Biol.Chem.. 274. 34657-34662 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miwa, K., et al.: "Therapeutic of an anti-Fas ligand mAb on lethal graftversus-host disease."Int.Immunol.. 11. 925-931 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Saito, I., et al.: "Fas ligand-mrdiated exocrinopathy resembling Sjogren's syndrome in mice transgenic for IL-10."J.Immunol.. 162. 2488-2494 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ikeda, A., et al.: "P300/CBP-dependent and-independent transcriptional interference between NK-kB RelA and p53."Biochem.Biophys.Res.Communs.. 272. 375-379 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ito, M., et al.: "Isoforms of JSAP1 scaffold protein generated through alternative splicing."Gene. 255. 229-234 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S-W.Kee, et al.: "Human Hepatitis B Virus X protein is a possible mediator of hypoxia induced angiogenesis in hepatocellular carcinoma."Biochem.Res.Communs.. 268. 456-461 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Dorjsuren, D.: "B型肝炎ウイルス(HBV)Xタンパクに拮抗する新規タンパクRMP。"実験医学. 18. 1137-1141 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] K.Masutomi, et.al,.: "Teromerase Activity Reconstituted in Vitro with Purified Human Teromerase Reverse Transcriptase and Human Teromerase RNA Component."J.Biol.Chem.. 275. 22568-22573 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 増富健吉: "昆虫細胞発現系を用いたヒトテロメアーゼ逆転写酵素(hTERT)の発現・精製。"バイオインダストリー. 17. 35-42 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Wei, W., et al.: "Direct interaction between the subunit RAP30 of TFIIF and RNA polymeras subunit5(RPB5)which contributes to the association between TFIIF and RNA polymerase II."J.Biol.Chem. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kuboki, Y., et al.: "A scaffold protein in the c-Jun NH2-terminal kinase signaling pathways suppresses the extracelller signal-regulated kinase signaling pathway."J.Biol.Chem.. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Qin, W., et.al.: "Mutational Analysis of the Structure and Functions of Hepatitis C Virus RNA-dependent RNA polymerase."Hepatol.. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 村上清史: "ヒトテロメアーゼ逆転写酵素(hTERT)の発現・精製とヒトテロメアーゼ活性の試験管内の再構成。"教育通信. (印刷中). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 村上清史: "ウイルス肝炎-最新情報「B型肝炎ウイルス(HVB)の遺伝子制御」"富士レビオ株式会社. 271 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] T.Nomura, et al.: "Human Hepatitis B virus X protein is detectable in nuclei of transfected cells, and active for transactivation."Biochim.Biophys.Acta. 1453. 330-340 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yul, DY., et al.: "Incidence of hepatocellular carcinoma in the transgenic mice expressing hepatitis B virus X-protein."J.Hepatol. 31. 123-132 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohno, H, et al.: "Human hepatitis B virus X protein augments the DNA binding of nuclear factor for IL-6 through its basic-leucine zipper domain."J.Med.Virol.. 58. 11-18 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Koyano, S., et al.: "A novel Jun N-terminal kinase(JNK)-binding protein that enhances the activation of JNK by MEK kinase1 and TGF-activated kinase1."FEBS Lett.. 475. 385-388 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takao, N., et al.: "Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation."Oncogene. 18. 7002-7009 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Zhang, Y., et al.: "Immunosuppressant FK506 activates NF-kB through the proteasome-mediated degradation of IkB."J.Biol.Chem.. 274. 34657-34662 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miwa, K., et al.: "Therapeutic effect of an anti-Fas ligand mAb on lethal graft-versus-host disease."Int.Immunol. 11. 925-931 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Saito, et al.: "Fas ligand-mediated exocrinopathy resembling Sjogren's syndrome in mice transgenic for IL-10."J.Immunol.. 162. 2488-2494 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kuwano, K., et al.: "Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis."J.Clin.Invest.. 104. 13-19 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.-W.Kee, et al.: "Human Hepatitis B Virus X protein is a possible mediator of hypoxia induced angiogenesis in hepatocellular carcinoma."Biochem.Biophys.Res.Communs.. 268. 456-461 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masutomi, K., et al.: "Telomerase Activity Reconstituted in Vitro with Purified Human Telomerase Reverse Transcriptase and Human Telomerase RNA Component."J.Biol.Chem.. 275. 22568-22573 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ikeda, A., et al.: "p300/CBP-dependent and-independent transcriptional interference between NF-kB RelA and p53."Biochem.Biophys. Res.Commun. 272. 375-379 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ito, M., et al.: "Isoforms of JSAP1 scaffold protein generated through alternative splicing."Gene. 255. 229-234 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kuboki, Y., et al.: "A scaffold protein in the c-Jun NH2-terminal kinase signaling pathways suppresses the extracellular signal-regulated kinase signaling pathways."J.Biol.Chem.. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Qin, W., et al.: "Mutational Analysis of the Structure and Functions of Hepatitis C Virus RNA-dependent RNA polymerase."Hepatol. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Wei, W., et al.: "Direct interaction between the subunit RAP30 of TFIIF and RNA polymerase subunit 5(RPB5)Which contributes to the association between TFIIF and RNA polymerase II."J.Biol.Chem.. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Murakami.: "Hepatitis B Virus X Protein : Structure, Function and Biology."Intervirol.. 42. 82-99 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tul,DY., et al.: "Incidence of hepatocellular carcinoma in the transgenic mice expressing hepatitis B virus X-protein."J.Hepatol.. 31. 123-132 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nomura,T., et al.: "Human Hepatitis B Virus X protein is detectable in nuclei of transfected cells, And active for transactivation."Biochim.Biophys.Acta.. 1453. 330-340 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohno,H., et al.: "Human Hepatitis B Virus X protein augments the DNA binding of nuclear Factor for IL & through its basic leucine zipper domain."J.Med.Viol.. 58. 11-18 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Murakami,S.: "Hepatitis B Virus X protein : Structure, Functions and Biological Roles."Intervirology. 42. 81-99 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] 村上清史: "B型肝炎ウイルスX蛋白の発現と機能"生化学. 71.11. 1309-1326 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kuwano,K., et al.: "Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis."J.Clin.Invest.. 104. 13-19 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Koyano,S., et al.: "A novel Jun N-terminal kinase (JNK)-binding protein that enhances the activation of JNK by MEK kinase 1 and TGF-activated kinase 1"FEBS Lett.. 457. 385-388 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ito,M.Et al.: "JSAP1, a novel Jun N-terminal kinase (JNK) that functions as a scaffold factor in the JNK signaling pathway."Mol.Cell.Biol.. 19. 7539-7548 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takao,N., et al.: "Disruption of ATM in p53-null cells causes multiple functional abnormalities in celllar response to ionizing radiation."Oncogene. 18. 7002-7009 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Zhang,Y., et al.: "Immunosuppressant FK506 activates NFkB through the proteasome-mediated degradation of IkB"J.Biol.Chem.. 274. 34657-34662 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miwa,K., et al.: "Therapeutic of an anti-Fas ligand mAb on lethal graftversus-host disease."Int.Immunol.. 11. 925-931 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Saito,I., et al.: "Fas ligand-mrdiated exocrinopathy resembling Sjogren's syndrome in mice transgenic for IL-10."J.Immunol.. 162. 2488-2494 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ikeda,A., et al.: "P300/CBP-dependent and-independent transcriptional interference between NK-kB RelA and p53."Biochem.Biophys.Res.Communs.. 272. 375-379 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ito,M., et al.: "Isoforms of JSAP1 scaffold protein generated through alternative splicing."Gene. 255. 229-234 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S-W.Kee, et al.: "Human Hepatitis B Virus X protein is a possible mediator of hypoxia induced angiogenesis in hepatocellular carcinoma."Biochem.Res.Communs.. 268. 456-461 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Dorjsuren,D.: "B型肝炎ウイルス(HBV)Xタンパクに拮抗する新規タンパクRMP。"実験医学. 18. 1137-1141 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Masutomi, et. al,.: "Teromerase Activity Reconstituted in Vitro with Purified Human Teromerase Reverse Transcriptase and Human Teromerase RNA Component."J.Biol.Chem.. 275. 22568-22573 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 増富健吉: "昆虫細胞発現系を用いたヒトテロメアーゼ逆転写酵素(hTERT)の発現・精製。"バイオインダストリー. 17. 35-42 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Wei,W., et al.: "Direct interaction between the subunit RAP30 of TFHF and RNA polymeras subunit5 (RPB5) which contributes to the association between TFHF and RNA polymerase II."J.Biol.Chem. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kuboki,Y., et al.: "A scaffold protein in the c-Jun NH2-terminal kinase signaling pathways suppresses the extracelller signal-regulated kinase signaling pathway."J.Biol.Chem.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Qin,W., et al.: "Mutational Analysisof the Structure and Functions of Hepatitis C Virus RNA-dependent RNA polymerase."Hepatol.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 村上清史: "ヒトテロメアーゼ逆転写酵素(hTERT)の発現・精製とヒトテロメアーゼ活性の試験管内の再構成。"教育通信. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 村上清史: "ウイルス肝炎-最新情報「B型肝炎ウイルス(HVB)の遺伝子制御」"富士レビオ株式会社. 271 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yul,DY.et al.: "Incidence of hepatocellular carcinoma in the transgenic mice expressing hepatitis B virus X-protein."J.Hepatol.. 31. 123-132 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nomura,T.,et al.: "Human Hepatitis B virus X protein is detectable in nuclei of transfected cells,and active for transactivation."Biochim.Biophys.Acta.. 1453. 330-340 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ohono,H.,et al.: "Human Hepatitis B Virus X protein augments the DNA binding of nuclear factor for IL & through its basic leucine zipper domain."J.Med.Virol.. 58. 11-18 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Murakami,S.: "Hepatitis B Virus X protein: Structure,Functions and Biological Roles."Intervirology. 42. 81-99 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kee,S.W.,et al.: "Human Hepatitis B Virus X protein is a possible mediator of hypoxia induced angiogenesis in hepatocellular carcinoma."Biochem.Biophys.Res.Communs.. (In printing). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 村上清史: "生化学 第71巻 第11号 B型肝炎ウイルスX蛋白の発現と機能"日本生化学会. 1309-1326 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 村上清史: "ウイルス肝炎ー最新情報「B型肝炎ウイルス(HBV)の遺伝子抑制」"富士レビオ株式会社. 271 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 村上清史: "最新医学 B型肝炎ウイルスX蛋白に拮抗する新規蛋白RMP"羊土社 (印刷中).

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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